scholarly journals Kaposi's Sarcoma-Associated Herpesvirus LANA Modulates the Stability of the E3 Ubiquitin Ligase RLIM

2019 ◽  
Vol 94 (5) ◽  
Author(s):  
Hagar Tadmor ◽  
Melanie Greenway ◽  
Anuj Ahuja ◽  
Ola Orgil ◽  
Gangling Liao ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Kaposi's Sarcoma ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Kaposi’S Sarcoma ◽  
Interacting Protein ◽  
Transcription Regulators ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
The Stability ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT The Kaposi’s sarcoma-associated herpesvirus (KSHV)-encoded latency-associated nuclear antigen (LANA) protein functions in latently infected cells as an essential participant in KSHV genome replication and as a driver of dysregulated cell growth. In a previous study, we have identified LANA-interacting proteins using a protein array screen. Here, we explore the effect of LANA on the stability and activity of RLIM (RING finger LIM-domain-interacting protein, encoded by the RNF12 gene), a novel LANA-interacting protein identified in that protein screen. RLIM is an E3 ubiquitin ligase that leads to the ubiquitination and degradation of several transcription regulators, such as LMO2, LMO4, LHX2, LHX3, LDB1, and the telomeric protein TRF1. Expression of LANA leads to downregulation of RLIM protein levels. This LANA-mediated RLIM degradation is blocked in the presence of the proteasome inhibitor, MG132. Therefore, the interaction between LANA and RLIM could be detected in coimmunoprecipitation assay only in the presence of MG132 to prevent RLIM degradation. A RING finger mutant RLIM is resistant to LANA-mediated degradation, suggesting that LANA promotes RLIM autoubiquitination. Interestingly, we found that LANA enhanced the degradation of some RLIM substrates, such as LDB1 and LMO2, and prevented RLIM-mediated degradation of others, such as LHX3 and TRF1. We also show that transcription regulation by RLIM substrates is modulated by LANA. RLIM substrates are assembled into multiprotein transcription regulator complexes that regulate the expression of many cellular genes. Therefore, our study identified another way KSHV can modulate cellular gene expression. IMPORTANCE E3 ubiquitin ligases mark their substrates for degradation and therefore control the cellular abundance of their substrates. RLIM is an E3 ubiquitin ligase that leads to the ubiquitination and degradation of several transcription regulators, such as LMO2, LMO4, LHX2, LHX3, LDB1, and the telomeric protein TRF1. Here, we show that the Kaposi’s sarcoma-associated herpesvirus (KSHV)-encoded LANA protein enhances the ubiquitin ligase activity of RLIM, leading to enhanced RLIM autoubiquitination and degradation. Interestingly, LANA enhanced the degradation of some RLIM substrates, such as LDB1 and LMO2, and prevented RLIM-mediated degradation of others, such as LHX3 and TRF1. In agreement with protein stability of RLIM substrates, we found that LANA modulates transcription by LHX3-LDB1 complex and suggest additional ways LANA can modulate cellular gene expression. Our study adds another way a viral protein can regulate cellular protein stability, by enhancing the autoubiquitination and degradation of an E3 ubiquitin ligase.

scholarly journals The Kaposi's Sarcoma-Associated Herpesvirus K5 E3 Ubiquitin Ligase Modulates Targets by Multiple Molecular Mechanisms

2007 ◽  
Vol 81 (12) ◽  
pp. 6573-6583 ◽  
Author(s):  
Robert E. Means ◽  
Sabine M. Lang ◽  
Jae U. Jung
Keyword(s):  
Cell Surface ◽  
Ubiquitin Ligase ◽  
Kaposi's Sarcoma ◽  
E3 Ubiquitin Ligase ◽  
Kaposi’S Sarcoma ◽  
Down Regulation ◽  
Class I Mhc ◽  
Mhc I ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Kaposi's sarcoma-associated herpesvirus encodes two highly related membrane-associated, RING-CH-containing (MARCH) family E3 ubiquitin ligases, K3 and K5, that can down regulate a variety of cell surface proteins through enhancement of their endocytosis and degradation. In this report we present data that while K5 modulation of major histocompatibility complex class I (MHC-I) closely mirrors the mechanisms used by K3, alternative molecular pathways are utilized by this E3 ligase in the down regulation of intercellular adhesion molecule 1 (ICAM-1) and B7.2. Internalization assays demonstrate that down regulation of each target can occur through increased endocytosis from the cell surface. However, mutation of a conserved tyrosine-based endocytosis motif in K5 resulted in a protein lacking the ability to direct an increased rate of MHC-I or ICAM-1 internalization but still able to down regulate B7.2 in a ubiquitin-dependent but endocytosis-independent manner. Further, mutation of two acidic clusters abolished K5-mediated MHC-I degradation while only slightly decreasing ICAM-1 or B7.2 protein destruction. This same mutant abolished detectable ubiquitylation of all targets. These data indicate that while K5 can act as an E3 ubiquitin ligase to directly mediate cell surface molecule destruction, regulation of its targets occurs through multiple pathways, including ubiquitin-independent mechanisms.

scholarly journals An Insight Into The Role of E3 ubiquitin Ligase c-Cbl, ESCRT Machinery and Host Cell Signaling in Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Entry and Trafficking

2017 ◽  
pp. JVI.01376-17 ◽  
Author(s):  
Binod Kumar ◽  
Arunava Roy ◽  
Mohanan Valiya Veettil ◽  
Bala Chandran
Keyword(s):  
Host Cell ◽  
Ubiquitin Ligase ◽  
Kaposi's Sarcoma ◽  
E3 Ubiquitin Ligase ◽  
Kaposi’S Sarcoma ◽  
Host Protein ◽  
Cell Surface Receptor ◽  
Signal Molecules ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

Kaposi's sarcoma-associated herpesvirus (KSHV)in vitroinfection of dermal endothelial cell begins with its binding to host cell surface receptor molecules such as heparan sulfate (HS), integrins (α3β1, αVβ3 and αVβ5), xCT and EphA2 receptor tyrosine kinase (EphA2R). These initial events initiate dynamic host protein-protein interactions involving a multi-molecular complex of receptors, signal molecules (FAK, Src, PI3-K, RhoA-GTPase), adaptors (c-Cbl, CIB1, Crk, p130Cas and GEF-C3G), and actin/myosin II light chain that leads to virus entry via macropinocytosis. Here we discuss how KSHV hijacks c-Cbl, an E3 ubiquitin ligase, to monoubiquitinate the receptors/actin which acts like markers for trafficking (similar to zip codes), resulting in the recruitment of the members of the host endosomal sorting complexes required for transport (ESCRT) Hrs, Tsg101, EAP45, CHMP 5 and 6 proteins (zip code readers) recognizing the ubiquitinated proteins and adaptors machinery to traffic through the different endosomal compartments in the cytoplasm to initiate the macropinocytic process and infection.

scholarly journals Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen dysregulates expression of MCL-1 by targeting FBW7

2021 ◽  
Vol 17 (1) ◽  
pp. e1009179
Author(s):  
Yeong Jun Kim ◽  
Yuri Kim ◽  
Abhishek Kumar ◽  
Chan Woo Kim ◽  
Zsolt Toth ◽  
...  
Keyword(s):  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
B Cell Lymphoma ◽  
Soft Agar ◽  
Nuclear Antigen ◽  
Ubiquitination Pathway ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
The Stability ◽  
Kaposi’S Sarcoma Associated Herpesvirus

Primary effusion lymphoma (PEL) is an aggressive B cell lymphoma that is etiologically linked to Kaposi’s sarcoma-associated herpesvirus (KSHV). Despite standard multi-chemotherapy treatment, PEL continues to cause high mortality. Thus, new strategies to control PEL are needed urgently. Here, we show that a phosphodegron motif within the KSHV protein, latency-associated nuclear antigen (LANA), specifically interacts with E3 ubiquitin ligase FBW7, thereby competitively inhibiting the binding of the anti-apoptotic protein MCL-1 to FBW7. Consequently, LANA-FBW7 interaction enhances the stability of MCL-1 by preventing its proteasome-mediated degradation, which inhibits caspase-3-mediated apoptosis in PEL cells. Importantly, MCL-1 inhibitors markedly suppress colony formation on soft agar and tumor growth of KSHV+PEL/BCBL-1 in a xenograft mouse model. These results strongly support the conclusion that high levels of MCL-1 expression enable the oncogenesis of PEL cells and thus, MCL-1 could be a potential drug target for KSHV-associated PEL. This work also unravels a mechanism by which an oncogenic virus perturbs a key component of the ubiquitination pathway to induce tumorigenesis.

scholarly journals Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 Targets MDM2 To Deregulate the p53 Tumor Suppressor Pathway

2009 ◽  
Vol 83 (13) ◽  
pp. 6739-6747 ◽  
Author(s):  
Hye-Ra Lee ◽  
Zsolt Toth ◽  
Young C. Shin ◽  
Jong-Soo Lee ◽  
Heesoon Chang ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Suppressor ◽  
Viral Replication ◽  
Ubiquitin Ligase ◽  
Kaposi's Sarcoma ◽  
E3 Ubiquitin Ligase ◽  
Growth Control ◽  
Kaposi’S Sarcoma ◽  
Kaposi’S Sarcoma Associated Herpesvirus ◽  
Cell Growth Control

ABSTRACT Cells infected by viruses utilize interferon (IFN)-mediated and p53-mediated irreversible cell cycle arrest and apoptosis as part of the overall host surveillance mechanism to ultimately block viral replication and dissemination. Viruses, in turn, have evolved elaborate mechanisms to subvert IFN- and p53-mediated host innate immune responses. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes several viral IFN regulatory factors (vIRF1 to vIRF4) within a cluster of loci, their functions being primarily to inhibit host IFN-mediated innate immunity and deregulate p53-mediated cell growth control. Despite its significant homology and similar genomic location to other vIRFs, vIRF4 is distinctive, as it does not target and antagonize host IFN-mediated signal transduction. Here, we show that KSHV vIRF4 interacts with the murine double minute 2 (MDM2) E3 ubiquitin ligase, leading to the reduction of p53, a tumor suppressor, via proteasome-mediated degradation. The central region of vIRF4 is required for its interaction with MDM2, which led to the suppression of MDM2 autoubiquitination and, thereby, a dramatic increase in MDM2 stability. Consequently, vIRF4 expression markedly enhanced p53 ubiquitination and degradation, effectively suppressing p53-mediated apoptosis. These results indicate that KSHV vIRF4 targets and stabilizes the MDM2 E3 ubiquitin ligase to facilitate the proteasome-mediated degradation of p53, perhaps to circumvent host growth surveillance and facilitate viral replication in infected cells. Taken together, the indications are that the downregulation of p53-mediated cell growth control is a common characteristic of the four KSHV vIRFs and that p53 is indeed a key factor in the host's immune surveillance program against viral infections.

scholarly journals NDRG1 facilitates lytic replication of Kaposi’s sarcoma-associated herpesvirus by maintaining the stability of the KSHV helicase

2021 ◽  
Vol 17 (6) ◽  
pp. e1009645
Author(s):  
Lianghui Dong ◽  
Jiazhen Dong ◽  
Min Xiang ◽  
Ping Lei ◽  
Zixian Li ◽  
...  
Keyword(s):  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Dna Helicase ◽  
Lytic Replication ◽  
Nuclear Antigen ◽  
Genome Replication ◽  
Transcription Activator ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
The Stability ◽  
Kaposi’S Sarcoma Associated Herpesvirus

The presumed DNA helicase encoded by ORF44 of Kaposi’s sarcoma-associated herpesvirus (KSHV) plays a crucial role in unwinding viral double-stranded DNA and initiating DNA replication during lytic reactivation. However, the regulatory mechanism of KSHV ORF44 has not been fully elucidated. In a previous study, we identified that N-Myc downstream regulated gene 1 (NDRG1), a host scaffold protein, facilitates viral genome replication by interacting with proliferating cell nuclear antigen (PCNA) and the latent viral protein latency-associated nuclear antigen (LANA) during viral latency. In the present study, we further demonstrated that NDRG1 can interact with KSHV ORF44 during viral lytic replication. We also found that the mRNA and protein levels of NDRG1 were significantly increased by KSHV ORF50-encoded replication and transcription activator (RTA). Remarkably, knockdown of NDRG1 greatly decreased the protein level of ORF44 and impaired viral lytic replication. Interestingly, NDRG1 enhanced the stability of ORF44 and inhibited its ubiquitin-proteasome-mediated degradation by reducing the polyubiquitination of the lysine residues at positions 79 and 368 in ORF44. In summary, NDRG1 is a novel binding partner of ORF44 and facilitates viral lytic replication by maintaining the stability of ORF44. This study provides new insight into the mechanisms underlying KSHV lytic replication.

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